It is estimated that, over the next twenty years, one in every five persons will be over the age of 65. With this new demographic profile will come an increase in a wide variety of age-related conditions, including Alzheimer's disease (“AD”) and other forms of dementia. Dementia is a syndrome of progressive decline, in multiple domains of cognitive function, that eventually leads to an inability to maintain normal social and/or occupational performance. At present, AD is the most common type of dementia, afflicting approximately 4 million Americans. One in ten persons over the age of 65, and nearly half of those over the age of 85, suffer from AD, and AD is the fourth leading cause of death in the U.S. The cost to American society is estimated to be at least $100 billion every year, making AD the third most costly disorder of aging.
Early identification is critical in progressive conditions such as AD, because earlier treatment may be more effective than later treatment in preserving cognitive function. Furthermore, early detection may allow time to explore options for treatment and care. Nevertheless, early detection is compromised by the failure of many patients to report to their treating physicians such early symptoms of AD as memory lapses and mild, but progressive, deterioration of specific cognitive functions, e.g., language (aphasia), motor skills (apraxia), and perception (agnosia). In addition, studies have documented the difficulty experienced by even well-trained health care professionals in correctly diagnosing AD and other forms of dementia (1). Accordingly, a simple, sensitive, reliable, and easily-administered AD diagnostic test would be of great assistance in targeting individuals for early intervention.
The earliest manifestation of AD is often memory impairment—a requirement in each of the two sets of criteria for diagnosis of dementia that are commonly used: the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria, which are specific for Alzheimer's disease, and the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria, which are applicable for all forms of dementia. Therefore, any test for AD or dementia that is associated with memory impairment should be most sensitive for the early detection of memory impairment.
Conventional memory tests are not optimal for the detection of mild dementia or the early stages of Alzheimer's disease. Some of these tests are inappropriately sensitive to the patient's educational level (2). They also may fail to test for certain types of memory loss that are typical of early dementia or AD. In addition, they may fail to reflect whether compounds or therapies that are administered to treat dementia have the desired effects. Furthermore, these tests frequently suffer from a high rate of false positives (low specificity).
Essentially all tests of memory, including tests of learning, retention, recall and/or recognition (hereinafter referred to as “memory tests”), involve serial-processing memory. “Serial-processing memory” acknowledges the limitations in a subject's input and output processing, which limitations permit the subject to process only one item at a time during input (receiving information) and output (recalling or retrieving information). In this sense, “memory” comprises units of received information and recalled information. In most tests of serial-processing memory, multiple items are presented serially to a subject, one item at a time, until all of the items have been presented (“serial presentation”), and the subject reports the remembered items serially, one item after another, in the order in which they were originally presented (“serial recall”). Items may be presented verbally, visually, or by any other suitable means.
Although there are many variations, a typical memory test consists of two main steps. First, the tester presents to the subject a number of items (e.g., bowl, zebra, orange, anger) to be recalled from memory. The items may be presented orally, in writing, in pictures, or by any other suitable means. Sometimes, the subject is also supplied with a cue associated with each or some of the items on the list. Typically, the cue is the category that encompasses the associated item, or that defines an aspect of the associated item. For example, the cue “animal” or “stripes” might be presented in association with the item “zebra”. Certain conventional, paired-associates tests use unrelated nouns as cues for test items.
The presentation of items in association with cues, wherein the subject first must identify an item from its cue, is known as “controlled learning”. Controlled learning is used in memory tests to ensure the attention of the subject and the equal processing of all of the items in a list. In addition, controlled learning demonstrates that the subject can identify items from their cues. Controlled learning also induces encoding specificity, by providing cues at the time of encoding information that later can be used to aid recall. The correct identification of items, by matching the items with their associated cues, verifies that the required processing was performed by the subject. Controlled learning may be performed by normal individuals, and by those with dementia or others type of cognitive decline.
In the next step, the subject is asked to recall the items presented to her in the list, either from memory, without presentation of the associated cue, in any order (free recall), or following presentation of the associated cue (cued recall). Cued recall may be used selectively to facilitate recall of those items not first recalled by free recall (recall in any order, without presentation of any cues).
One variation of the standard memory test involves an additional step for “controlled rehearsal”, wherein the subject is instructed to repeat each item as it is presented. Alternately, the subject may be asked to repeat the preceding item as the current item is presented, or the subject may be instructed to repeat both the preceding item and the current item. As with controlled learning, controlled rehearsal ensures the attention of the subject and the equal processing of all items, and demonstrates that the required processing was performed by the subject.
Some memory tests, particularly tests of delayed recall or forgetfulness, utilize interference delays between memory trials. Interference delays are periods of time between memory trials, wherein an unrelated task (e.g., counting, spelling) is performed by the subject to prevent rehearsal. As another alternative, the tester may maintain a constant number of items to be learned by the subject. This step, referred to as “contingent learning”, can be accomplished by adding new items to the list as the old items are learned.
“Controlled reminding” refers to an additional step wherein the subject is reminded of items that were not recalled during each trial. In free-recall memory tests, the subject is not reminded of the items that were not recalled until after he has been given the opportunity to recall as many items as possible. In the case of cued recall, the subject is reminded of the item before the next cue is presented. Controlled reminding may be either “selective reminding”, wherein the subject is reminded each time the item is not recalled, or “restricted reminding”, wherein the subject is reminded only until the item is recalled once, either with or without presentation of the item.
Memory tests known in the art include various combinations of the foregoing elements and steps. For example, the memory component of the Free and Cued Selective Recall Test (“FCRST”) comprises an initial controlled-learning step, wherein the patient first must identify items from their associated cues. The patient then must recall as many of the test items as possible (typically sixteen) from their associated category cues. Following a brief interference delay, the patient is then asked to recall as many of the presented items as she can by free recall (i.e., recall in any order, without the associated cues), followed by cued recall for items not remembered by free recall. If there are multiple trials, the subject is then selectively reminded of missed items (i.e., reminded each time an item is not recalled) before the next recall trial. The score for total recall is the total of uncued responses and cued responses, with each response (whether cued or uncued) worth one point.
Conventional memory tests are scored by tallying the total number of items recalled from a list of items previously presented to the subject, either within any one testing trial or across many testing trials. Each item recalled is accorded the same weight—a method known as “unit counting” or “unweighted counting”—so that a subject recalling items 1 to 5 of a ten-item list would be judged to have the same measure of memory as a subject who recalled items 6 to 10 of the same ten item list. Furthermore, a subject recalling items 1 to 5 of a ten-item list in a first trial, and items 6 to 10 of the list in a second trial, would be considered to have the same measure of memory as a subject who recalled items 1 to 5 in the first and second trials, but could not recall items 6 to 10 at all. Memory tests utilizing this type of unweighted counting assume that all of the items presented and retrieved are equal in value, i.e., that the probability of encoding, learning, and retaining any single item is equal to the probability of encoding, learning, and retaining any other items.
However, items in a presented list differ in likelihood of recall, depending upon a number of factors. Serial processing at input and output often results in “serial-position effects”, which are differences in the frequency of recall among list items due to the order in which the items are presented. In this regard, some items are “easier” or “more difficult” to recall, depending upon the order in which such items are presented to the subject. These serial-position effects are illustrated for test groups in serial-position curves, which are graphs that show the percentage of subjects recalling the items of a list versus the order in which the items are presented or recalled.
Serial-position effects demonstrate that the probability of recall may be affected by the order in which test items are presented (“presentation order”), or the order in which test items are recalled (“recall order”), or both. Important serial-position effects include “primacy”, in which there is a higher recall of earlier presented items, and “recency”, in which there is a higher recall of the items most recently presented. An analysis of serial-position effects is important because the manifestation of certain serial-position effects (or the lack thereof) may be associated with dementia. For instance, recall by normal aged subjects is characterized by both primacy and recency effects, whereas recall by aged subjects with AD is characterized only by recency effects.
Additionally, unweighted counting disregards qualitative differences in memory impairment, e.g., where impairment in total memory is a result of deficiencies in a particular stage or facet of the memory process, such as a deficiency in encoding information, learning information, or retaining information. Such qualitative differences may be essential for the diagnosis of AD or dementia characterized by memory impairment, and may be instrumental in ensuring the appropriate targeting of, and evaluation of the efficacy of, therapeutics directed to the treatment of AD or early dementia.
In view of the foregoing, the measurement of memory by unweighted counting (unit weighting) may not be justified. Although unweighted counting provides a lower bound for memory performance, it sacrifices statistical power by disregarding essential information about the serial-position characteristics of retrieved items (including probability of retrieval), and about the various processes involved in memory (including encoding, learning, and retention). A method of measuring memory that preserves information about the serial-position effects of retrieved items, or that recognizes deficiencies in certain elements of total memory, would improve the assessment of memory performance, aid in the earlier diagnosis of AD and dementia, and permit the sophisticated screening of therapeutics directed to the treatment of AD and dementia.